Tele amination

As mentioned previously, only in the amination reaction of 4-piperidino-5-bromopyrimidine was an SnH tele amination observed. Besides the 6-amino-4-piperidinopyrimidine, a small amount of 2-amino-4-piperidinopy-rimidine was isolated. Its formation is depicted in Scheme 11.29. The formation of this compound can be considered as additional proof of the vulnerability of position 2 in the pyrimidine ring for nucleophilic attack, as observed in the formation of 52. 

ChIoro-2-phenyl-5-R-pyrimidines (R = MeO, EtO, MeS, C6HS) undergo conversion to 4-amino-2-phenyl-5-R-pyrimidines.104 Here, attachment at position 6 also occurs as a first step of this seemingly simple reaction. It has, in fact, been shown that the replacement of chlorine is not direct but consists of a tele amination reaction. 

The amination reaction carried out at -33°C gives a mixture consisting of 4-amino-, 8-amino-, and 2-amino-1,7-naphthyridine, 4-amino-2-methyl-1,3,7-triazanaphthalene, and some unsubstituted 1,7-naphthyridine. The composition of this mixture is not related to that of the adducts described above in any simple way. Adducts 54 and 56 are suggested to be involved in the formation of the 8-amino and 4-amino derivatives, respectively, by a tele-amination mechanism.111 Scheme 3 illustrates one of these proposed paths. 

Under these conditions the amination reaction yields a mixture of 2-amino- and 8-amino-1,7-naphthyridines in a nearly 1 1 ratio. Here again the observed a-adduct is responsible for the formation of only one of the products, the 2-amino compound, which arises by a tele amination mechanism. The other amine requires some other as yet undetected a-adduct.111... 

Amination of 5-bromo-l,6-naphthyridine (113) gives as tele product 2-amino-l,6-naphthyridine (51 ),24 but in addition to the intermediacy of anionic cr-adduct (114) (as proved by H-NMR spectroscopy), its formation involves anionic cr-adduct 115, which is formed by a proton shift from 114. The number of atoms between positions 2 and 5 is five, thus this reaction is referred to as an odd tele substitution. Both types of tele substitution involve Addition of the nucleophile as the initial step and Elimination of the leaving group as the last step. However, in the even tele substitution the elimination can be described to take place from a neutral dihydro species, while in the odd tele substitution the elimination must occur from an anionic intermediate. In the naphthyridines several examples of even and odd tele substitutions are found, and in the following sections the results of studies concerned with tele amination are presented. 

It has been reported that 2-bromo(chloro)-l,7-naphthyridine (22) with KNH2/NH3 gives 4-amino-2-methyl-l,3,7-triazanaphthalene (162),25 in addition to 2-amino-l,7-naphthyridine (53) and two tele amination products, 4-amino-(55) and 8-amino-1,7-naphthyridine (54). 

Amination of 5-bromo-l,7-naphthyridine with potassium amide in liquid ammonia gave a small yield of a normal Chichibabin product, 8-amino-5-bromo-l,7-naphthyridine, along with tele-aminated products 8-amino- and 2-amino-l,7-naphthyridine. 5-Chloro-I,7-naphthyridine (202) gave a low yield of 8-amino-5-chloro-l,7-naphthyridine (203) and other unidentified products (Scheme 71) (78JHC731). 

Among the many compounds formed in low yield by treatment of 2-chloro- or 2-bromo-l,7-naphthyridine with potassium amide is also the product of a ring transformation with concurrent tele amination, 2-methylpyrido[3,4-[Pg.193]

In chronological order, the next milestones in research were the studies by Fukuda and Utimoto on the addition of nucleophiles (water, alcohols and amines) to alkynes [13]. A decade later, Teles obtained notable turnover numbers (TONs) and turnover frequencies (TOFs) in the addition of alcohols to alkynes [14]. 

Solvent-free conditions were used by Tanaka et al. in their assays to obtain intermolecular reactions from alkynes and anilines. The chosen catalyst was [AuMe(PPh3)] with an acidic promoter [92]. Reaction, whose effectiveness was greater in the case of aromatic amines, proceeded via Markovnikov by amine electrophilic attack of the alkyne in a similar way to the methanol addition proposed by Teles (see Section 2.1.3.2) and provided high yields and TONs. 

Substitution with amine nucleophiles in the series of chlorotoluene complexes showed that the substitution is direct no cine or tele substitution was observed.75 The analogous [(fluoroarene)FeCp]+ complexes are known, but less well developed. Kinetic studies show that the fluoro derivatives are more reactive compared to the chloro analogs.47... 

One example has been reported of the occurrence of an even tele substitution within one ring of the 1,7-naphthyridine system. Amination of 5-halogeno-l,7-naphthyridines (27) with potassium amide gave 8-amino-1,7-naphthyridine (54).28 This reaction bears a close analogy to the formation... 

Tele substitutions that occur with the halogen derivatives of naphthy-ridines, which are characterized by a high degree of symmetry, cannot simply be recognized by the structure of the products obtained. For example, the amination of l-halogeno-2,6-naphthyridines (121, R = H)yields 1-amino-2,6-naphthyridine (123 R = H) (5-amino-2,6-naphthyridine 60).21 It is evident that this compound can be formed either by an Sm(AE) ps0 or SN(AE),elc pathway or by both mechanisms. 

An odd tele substitution also occurring in one ring has been observed on amination of 2-bromo-l,5-naphthyridine, yielding 4-amino-1,5-naphthyridine.21... 

An interesting case of an odd tele substitution has been found when aminating 2-X-l,8-naphthyridine (X = Cl, Br) with liquid ammonia containing potassium amide.10 29,30 The product obtained in the amination was 2-(or 7-) amino-1,8-naphthyridine (58). However, carrying out the amination with 2-X-7-deutero-l,8-naphthyridine (138), the 2-amino product had a deuterium content considerably less than was present in the starting material. From the amount of deuterium present in the 2-amino compound, it was calculated that for X = Br, 45% of the amino compound was formed according to the SN(AE) ele process and that for X = Cl, this percentage was considerably lower (10%).58... 

There is general consensus on the fact that the endogenous agonist histamine, 2-(imidazole-4-yl)ethylamine, binds to the receptor in its monocationic state (protonated at the side chain amine group). The monocationic form is predominantly (96.6%) present at pH 7.4 [11]. In this state, the neutral imidazole ring can exist in two different tautomeric forms, denominated by proximal (it) and tele (x), respectively (Figure 1). 

Also in the activation of alkynes for nucleophilic attack, gold salts prove to be soft, exceptionally carbophilic Lewis acids, as confirmed by the examples shown in Scheme 3 [10]. According to Utimoto and Fukuda both the addition of water as well as of amines to alkynes are catalyzed by gold(III) salts, in particular by sodium tetrachloroaurate ketones such as 8 and imines such as the ant toxin 10 are obtained as products in excellent yields [10a-e]. In the cyclization reaction giving the 1,4-dioxane 12 developed by Teles et al.,... 

Chloro-l,7-naphthyridine (110 X = Cl) gives on amination with KNHj/ NH3 the tele product 2-amino-1,7-naphthyridine (53) in addition to the ipso product 8-amino-l,7-naphthyridine (54). The formation of 53 involves as intermediates anionic a-adduct 111 (X = Cl) (its existence has been proved by NMR spectroscopy see Section II,Bd) and probably 2-amino-2,8-dihydro-8-chloro-1,7-naphthyridine (112). The latter undergoes a base-catalyzed dehydrochlorination, yielding 53. Because there are four atoms between position 2 and 8, the reaction is called an even tele substitution. 

One example has been reported of the occurrence of an even tele substitution within one ring of the 1,7-naphthyridine system. Amination of... 

A good illustration of the te/e-amination reactions is interaction of 5-bromo-l,7-naphthyridine with KNH2 in liquid ammonia, leading to a mixture of 8-amino- and 2-amino-1,7-naphthyridines in 42 and 3% yields, respectively (Scheme 59) [126]. During the reaction the amide ion attacks C-2 and C-8 atoms, which are activated by the adjacent aza groups. The intermediate hydrogen bromide. Two excellent reviews on the tele-substitution reactions were published in 2001 and 2011 [104, 127]. 

An important breakthrough was made between 1991 and 2000 when Utimoto et al. and Teles et al. first reported that alkynes could be functionalized by an inter- or intramolecular addition of water, alcohols, and amines in the presence of a gold(III) salt or a eationic gold(I) complex (Scheme 16.2, Eqs. 1-3) [4]. This significant advance was followed by the work of Hashmi et al. [5] who demonstrated in 2000 that AUCI3 could be used as an efficient catalyst for the intramolecular addition of ketones and alcohols to alkynes and for the inter- or intramolecular arylation of alkynes and allenes (Scheme 16.2, Eqs. 4 and 5). 

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